The present invention is in the field of compositions of matter, and pharmaceutical compositions and methods of treatment utilizing one or more of said compositions of matter as the active ingredient and the active agent with respect thereto, wherein said composition of matter comprises an indazole as an essential feature of its overall chemical structure, said indazole constituting a bioisosteric replacement of a catechol or functional derivative thereof.
The catechol-containing as well as the indazole-based compositions of matter have biological activity as selective inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), and as such are useful in the treatment of asthma, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, dermatitis, Crohn""s disease, arthritis, and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF. This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Since the recognition that cyclic adenosine phosphate (AMP) is an intracellular second messenger, E. W. Sutherland, and T. W. Rall, Pharmacol. Rev., 12, 265, (1960), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized, J. A. Beavo et al., TiPS, 11, 150, (1990), and their selective inhibition has led to improved drug therapy, C. D. Nicholson, M. S. Hahid, TiPS, 12, 19, (1991). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release, M. W. Verghese et al., J. Mol. Cell Cardiol., 12 (Suppl. II), S 61, (1989) and airway smooth muscle relaxation (T. J. Torphy in xe2x80x9cDirections for New Anti-Asthma Drugs,xe2x80x9d eds S. R. O""Donnell and C. G. A. Persson, 1988, 37 Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
TNF is recognized to be involved in many infectious and auto-immune diseases, W. Friers, FEBS Letters, 285, 199, (1991). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock, C. E. Spooner et al., Clinical Immunology and Immunopathology, 62, S11, (1992). The role of these mediators in the pathogenesis of Crohn""s disease is discussed in Van Hogezand, R. A. and Verspaget, H. W., Drugs, 56(3), 299-305 (1998).
The present invention is concerned with the discovery that the indazole nucleus is a moiety which is capable of being a bioisostere replacement for the catechol moiety which is an essential part of endogenous ligands acting on phosphodiesterase-4 receptors and thereby carrying out essential metabolic functions in the body. The indazole nucleus is also a bioisostere replacement for the catechol moiety which is an essential part of numerous drugs which have been and in the future will be created and developed for therapeutic treatments as detailed further herein. This bioisostere replacement will be better understood from the following structural representation of the catechol moiety and the indazole moiety which replaces it: 
The terms xe2x80x9cbioisosterexe2x80x9d, xe2x80x9cbioisosteric replacementxe2x80x9d, xe2x80x9cbioisosterismxe2x80x9d and closely related terms as used herein have the same meanings as those generally recognized in the art. Bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density. Bioisosterism arises from a reasonable expectation that a proposed bioisosteric replacement will result in maintenance of similar biological properties. Such a reasonable expectation may be based on structural similarity alone. This is especially true in those cases where a number of particulars are known regarding the characteristic domains of the receptor, etc. involved, to which the bioisosteres are bound or which works upon said bioisosteres in some manner.
Phosphodiesterase-4 is a cAMP-specific phosphodiesterase which plays an important role in the regulation of inflammatory and immune cell activation. A significant variety of different structural types of compounds active as PDE-4 inhibitors has been reported, and PDE isozymes have been characterized in cardiac muscle, and airway and arterial smooth muscles. Attention has also been focused on a high-affinity allosteric binding site which is abundant in brain PDE4 isozyme, whose differential modulation relative to the cAMP catalytic site has yielded drugs with greater therapeutic utility. Rolipram, which contains catechol as a key part of its overall chemical structure, is representative of this type of PDE4 inhibitor and may be depicted as follows: 
Accordingly, there is disclosed herein a substantial number of indazole-containing compositions of matter which are PDE4 inhibitors and which are the result of a bioisostere replacement of catechol from a compound which originally contained said catechol moiety and which also had PDE4 inhibitor activity. However, there is also disclosed herein a number of catechol-containing compounds which are PDE4 inhibitors and which are also suitable to be subjected to indazole bioisostere replacement in accordance with the present invention. These latter compounds are claimed both as novel indazole compositions of matter and as the products of indazole bioisostere replacement in accordance with the present invention.
The present invention relates to compounds having therapeutic usefulness based on their activity as phosphodiesterase-4 inhibitors, comprising an indazole as one essential component of their overall chemical structure, wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound or compounds having the same said therapeutic usefulness based on possession of phosphodiesterase-4 inhibitor activity, as well as having the same remaining said components which make up the overall chemical structure of the compound(s) involved.
In particular, the present invention relates to the above-described compounds which are therapeutically useful in treating or preventing asthma.
The present invention thus also relates to an improved method of treating asthma using a known compound having a catechol moiety or functional derivative thereof as one essential component of its overall chemical structure; wherein the improvement consists of using a compound having an indazole moiety as one essential component of its overall chemical structure and having the same remaining said components of its overall chemical structure, wherein said indazole moiety constitutes a bioisosteric replacement for said catechol moiety.
The present invention further relates to a compound (a) useful as a therapeutically active agent in a therapeutically effective amount for a method of treating or preventing; and (b) useful as an active ingredient in a pharmaceutical composition for treating or preventing: one or members selected from the groups of diseases and conditions consisting essentially of (1) inflammatory comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn""s disease; (2) respiratory comprising: acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD) including asthma, chronic bronchitis and pulmonary emphysema, and silicosis; (3) infectious comprising: sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) general comprising: bone resorption diseases; reperfusion injury; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infectioin, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia; wherein said compound comprises an inhibitor of phosphodiesterase isozyme 4 (PDE4) and wherein an indazole is one essential component of said compound""s overall chemical structure, and wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound having the same said one or more types of therapeutic activity and the same remaining said components of its overall chemical structure.
Especially important among the above-recited diseases and conditions which may be treated or prevented using the compounds of the present invention are the inflammatory diseases and conditions and the respiratory diseases and conditions. Among the inflammatory diseases and conditions which are especially significant with regard to successful treatment or prevention using the compounds of the present invention comprise: joint inflammation, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. Among the respiratory diseases and conditions which are especially significant with regard to successful treatment or prevention using the compounds of the present invention comprise: asthma, acute respiratory distress syndrome, and bronchitis.
The present invention relates to novel compositions of matter and to therapeutic agents and active ingredients useful in treating or preventing one or members selected from the groups of diseases and conditions as above-described, comprising a compound of Formula (IA) or (IB): 
and to pharmaceutically acceptable salts thereof, wherein:
R is a member independently selected from the group consisting essentially of hydrogen, (C1-C9)alkyl; xe2x80x94(CH2)n(C3-C10) cycloalkyl wherein n is an integer selected from 0, 1, and 2; (C1-C6)alkoxy(C1-C6)alkyl; xe2x80x94(C2-C6)alkenyl; xe2x80x94(CH2)n(C3-C9) heterocyclyl wherein n is an integer selected from 0, 1, and 2; and xe2x80x94(Z1)b(Z2)c(C6-C10) aryl wherein b and c are integers independently selected from 0 and 1, Z1 is (C1-C6) alkylene or (C2-C6) alkenylene, and Z2 is O, S, SO2, or NR119; and further wherein said heterocyclyl is a member independently selected from the group consisting essentially of acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl; wherein said aryl is a carbocyclic moiety which is a member independently selected from the group consisting essentially of benzyl; cis- and trans-decahydronaphthalenyl; 2,3-1H-dihydroindenyl (indanyl); indenyl; 1-naphthalenyl; 2-naphthalenyl; phenyl; and 1,2,3,4-tetrahydronaphthalenyl; wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties defining said R groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; (C1-C5) alkyl; (C2-C5) alkenyl; (C1-C5) alkoxy; (C3-C6) cycloalkoxy; mono-, di-, and tri-fluoromethyl; nitro; xe2x80x94C(xe2x95x90O)OR119, xe2x80x94C(xe2x95x90O)NR119R120, xe2x80x94NR119R120 and xe2x80x94S(xe2x95x90O)2 NR119R120;
R1 is a member independently selected from the group consisting essentially of hydrogen; (C1-C9)alkyl; (C2-C3)alkenyl; phenyl; (C3-C7)cycloalkyl; and (C3-C7) cycloalkyl(C1-C2)alkyl; wherein said alkyl, alkenyl and phenyl moieties defining said R1 groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of methyl; ethyl; mono-, di-, and tri-fluoromethyl; and bromo, chloro, or fluoro; and
R2a and R2b are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R2a and R2b must be independently selected as hydrogen, wherein said substituents comprise moieties of the groups (I) through (V) summarized below, including those of the partial Formulas therein set out, all as defined in detail herein:
I
a moiety of partial Formulas (IC), (ID), (IE), or (IF): 
II
a member selected from the group consisting essentially of R229; xe2x80x94C(xe2x95x90O)NR222(CHR222)mC(xe2x95x90O)NR222O(CH2)q(C6-C10)aryl); xe2x80x94C(xe2x95x90NR242)NH(CH2)p(C6-C10) aryl; xe2x80x94C(xe2x95x90O)NR218(CHR222)mC(xe2x95x90O)NR222(CH2)pOR222; xe2x80x94C(xe2x95x90O)NR222(CHR222)mS(C1-C4) alkyl; xe2x80x94C[xe2x95x90NOC(xe2x95x90O)R235]R236; xe2x80x94CR227R228CHR238NR219SO2(CH2)pA; xe2x80x94CR227R228CHR238NR219P(xe2x95x90O)(OR222)C(xe2x95x90O)(C1-C4)alkyl; xe2x80x94CR227R238CHR238NR219P(xe2x95x90O)[(C1-C4) alkoxy]2, xe2x80x94Z3xe2x80x94R217; and xe2x80x94(CR227R228)mNR219(C(O))qR220 wherein p is an integer selected from 0, 1, and 2; m is an integer selected from 1, 2, 3, 4, 5, and 6; and q is an integer selected from 1 and 2;
xe2x80x94OR, a moiety of partial Formulas (IIA) through (III), inclusive: 
III
a member independently selected from the group consisting essentially of 2-oxo-4-pyrrolyl; pyrazolyl; 2-oxo-3,4-dihydro-5-pyrimidyl; 2-oxo-3,4-dihydro4-pyrimidyl; 2-oxo-tetrahydro-4-pyrimidyl; 2-oxo-tetrahyro-5-pyrimidyl; 2-oxo4-pyrimidyl; and 2-oxo-5-pyrimidyl; wherein each of said R2a and R2b groups is substituted by 0, 1, 2, 3, or 4 R236 groups;
xe2x80x94OR, a moiety of partial Formulas (IIIA) through (III), inclusive: 
IV 
a moiety of partial Formulas (VA) through (VM), inclusive: 
The present invention relates to a novel class of therapeutically active compositions of matter and member species thereof comprising indazole-containing compounds having PDE4 inhibitory activity which are produced by an indazole-for-catechol bioisostere replacement. In particular, the novel compositions of matter of the present invention comprise a compound of Formula (IA) or (IB): 
and to pharmaceutically acceptable salts thereof, wherein:
R is a member independently selected from the group consisting essentially of hydrogen, (C1-C9)alkyl; xe2x80x94(CH2)n(C3-C10)cycloalkyl wherein n is an integer selected from 0, 1, and 2; (C1-C6)alkoxy(C1-C6)alkyl; (C2-C6)alkenyl; xe2x80x94(CH2)n(C3-C9)heterocyclyl wherein n is an integer selected from 0, 1, and 2; and xe2x80x94(Z1)b(Z2)c(C6-C10) aryl wherein b and c are integers independently selected from 0 and 1, Z1 is (C1-C6)alkylene or (C2-C6) alkenylene, and Z2 is O, S, SO2, or NR119; and further wherein said heterocyclyl is a member independently selected from the group consisting essentially of acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzoblbfuranyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; soquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl; wherein said aryl is a carbocyclic moiety which is a member independently selected from the group consisting essentially of benzyl; cis- and trans-decahydronaphthalenyl; 2,3-1H-dihydroindenyl (indanyl); indenyl; 1-naphthalenyl; 2-naphthalenyl; phenyl; and 1,2,3,4-tetrahydronaphthalenyl; wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties defining said R groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; (C1-C5)alkyl; (C2-C5)alkenyl; (C1-C5)alkoxy; (C3-C6)cycloalkoxy; mono-, di-, and tri-fluoromethyl; nitro; xe2x80x94C(xe2x95x90O)OR119, xe2x80x94C(xe2x95x90O)NR119R120, xe2x80x94NR119R120 and xe2x80x94S(xe2x95x90O)2NR119R120;
R1 is a member independently selected from the group consisting essentially of hydrogen; (C1-C9) alkyl; (C2-C3) alkenyl; phenyl; (C3-C7) cycloalkyl; and (C3-C7) cycloalkyl(C1-C2) alkyl; wherein said alkyl, alkenyl and phenyl moieties defining said R1 groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of methyl; ethyl; mono-, di-, and tri-fluoromethyl; and bromo, chloro, or fluoro; and
R2a and R2b are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R2a and R2b must be independently selected as hydrogen, wherein said substituents comprise moieties of the groups (I) through (V):
I
a moiety of partial Formulas (IC), (ID), (IE), or (IF): 
wherein the dashed lines in formulas (IC) and (ID) independently and optionally represent a single or double bond, provided that in formula (IC) both dashed lines cannot both represent double bonds at the same time;
m is an integer selected from 0, 1, 2, 3, and 4, and when 2, may apply to a single carbon atom on the ring;
R113 is a member selected from the group consisting essentially of H; bromo, chloro, or fluoro; cyano; (C2-C4)alkynyl substituted by 0 or 1 substituent where said substituent is a member selected from the group consisting essentially of phenyl, pyridyl and pyrimidinyl; (C1-C4) alkyl substituted by 0 to 6 bromo, chloro, or fluoro; xe2x80x94CH2NHC(xe2x95x90O)C(xe2x95x90O)NH2; cyclopropyl substituted by 0 or 1 substituent where said substituent is a member selected from the group consisting essentially of R121; R127; CH2OR119; NR119R120; CH2NR119R120; C(xe2x95x90O)OR119; C(xe2x95x90O)NR119R120; Cxe2x89xa1CR11; C(Z)H; and xe2x80x94CHxe2x95x90CR121R121; provided that R113 is H in Formula (IC) when the dashed line for the ring carbon of R113 attachment represents a double bond;
R114 is a member selected from the group consisting essentially of H; R116; C(Y)R124; C(xe2x95x90O)OR124; C(Y)NR127R124; CN; C(NR127)NR127R124; C(NOR119)R124; C(xe2x95x90O)NR119NR119C(xe2x95x90O)R119; C(xe2x95x90O)NR119NR127R124; C(NOR124)R119; C(NR119)NR127R124; C(NR124)NR119R120; C(NCN)NR127R124, C(NCN)S(C1-C4) alkyl; CR119R120OR124, CR119R120SR124, CR119R120S(O)nR125 where n is an integer selected from 0, 1, and 2; CR119R120NR124R127; CR119R120NR127S(xe2x95x90O)2R15; CR119R120NR127C(Y)R124; CR119R120NR127C(xe2x95x90O)OR125; CR119R120NR127C(Y)NR127R124; CR119R120NR127C(NCN)NR127R124; CR119R120NR127C(CR119NO2)S(C1-C4)alkyl; CR119R120C(xe2x95x90O)OR125; CR119R120C(Y)NR127R124; CR119R120C(NR127)NR127R124; CR119R120CN; CR119R120C(NOR120)R124; CR119R120C(NOR124)R120; CR119R120NR127C(NR127)S(C1-C4) alkyl; CR119R120NR127C(NR127)NR127R124; CR119R120NR127C(xe2x95x90O)C(xe2x95x90O)NR127R124; CR119R120NR127C(xe2x95x90O)C(xe2x95x90O)OR24; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; CR119R120(tetrazolyl); CR119R120(thiazolyl); CR119R120(imidazolyl); CR119R120(imidazolidinyl); CR119R120(pyrazolyl); CR119R120(thiazolidinyl); CR119R120(oxadiazolyl); CR119R120(oxazolidinyl); CR119R120(triazolyl); CR119R120(isoxazolyl); CR119R120(oxadiazolyl); CR119R120(thiadiazolyl); CR119R120(morpholinyl); CR119R120(piperidinyl); CR119R120(piperazinyl); and CR119R120(pyrrolyl); said heterocyclic groups being substituted by 0 to 3 substituents R124;
R115 is a member selected from the group consisting essentially of R119; OR119; xe2x80x94CH2OR119; cyano; C(xe2x95x90O)R119; C(xe2x95x90O)OR119; C(xe2x95x90O)NR119R120; and NR119R120; provided that R115 is absent when the dashed line in Formula (9.2) represents a double bond;
or R114 and R115 are taken together to form xe2x95x90O or xe2x95x90R118;
or R115 is hydrogen and R114 is OR124; SR124; S(O)nR125, where n is an integer selected from 0, 1, and 2; S(xe2x95x90O)2NR127R124; NR127R124; NR124C(xe2x95x90O)R119; NR127C(Y)R124; NR127C(xe2x95x90O)OR125; NR127C(Y)NR127R124; NR127S(xe2x95x90O)2NR127R124; NR127C(NCN)NR127R124; NR127S(xe2x95x90O)2R125; NR127C(CR119NO2)NR127R124; NR127C(NCN)S(C1-C4) alkyl; NR127C(CR119NO2)S(C1-C4) alkyl; NR127C(NR127)NR127R124; NR127C(xe2x95x90O)C(xe2x95x90O)NR127R124; or NR127C(xe2x95x90O)C(xe2x95x90O)OR124;
R116 is a member independently selected from the group consisting essentially of methyl and ethyl substituted by 0 to 5 bromo, chloro, or fluoro, wherein m may be 2 with respect to a single ring carbon atom to which R116 is attached;
R117 is a member independently selected from the group consisting essentially of OR124; SR124SO2NR127R124; NR127R124; NR124C(xe2x95x90O)R119; NR127C(Y)R124; NR127C(xe2x95x90O)OR125; S(O)nR12 where n is an integer selected from 0, 1, and 2; OS(xe2x95x90O)2R122; OR122; OC(xe2x95x90O)NR123R122; OC(xe2x95x90O)R123; OC(xe2x95x90O)OR123; O(CR122R123)mOR122 where m is an integer selected from 0, 1, and 2; CR119R120OR124; CR119R120NR127R124; C(Y)R124; C(xe2x95x90O)OR124; C(Y)NR127R124; CN; C(NR127)NR127 R124; C(NOR119)R124; C(xe2x95x90O)NR119NR119C(xe2x95x90O)R119; C(xe2x95x90O)NR119NR127R124; C(NOR124)R119; C(NR119)NR127R124; C(NR124)NR119R120; C(NCN)NR127R124; C(NCN)S(C1-C4) alkyl; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; and thiadiazolyl; where the recited heterocyclic groups are substituted by 0 to 3 substituents where said substituent is R124;
R118 is a member independently selected from the group consisting essentially of xe2x80x94NR 125; xe2x80x94NCR119R120(C2-C6)alkenyl; xe2x80x94NOR124; xe2x80x94NOR129; xe2x80x94NOCR119R120(C2-C6) alkenyl; xe2x80x94NNR119R124; xe2x80x94NNR119R129; xe2x80x94NCN; xe2x80x94NNR119C(Y)NR119R124; xe2x80x94C(CN)2; xe2x80x94CR124CN; xe2x80x94CR124C(xe2x95x90O)OR119; xe2x80x94CR124C(xe2x95x90O)NR119R124; xe2x80x94C(CN)NO2; xe2x80x94C(CN)C(xe2x95x90O)O(C1-C4) alkyl; xe2x80x94C(CN)OC(xe2x95x90O)O(C1-C4) alkyl; xe2x80x94C(CN)(C1-C4)alkyl; xe2x80x94C(CN)C(xe2x95x90O)NR119R124; 2-(1,3-dithiane), 2-(1,3-dithiolane), dimethylthio ketal, diethylthio ketal, 2-(1,3-dioxolane), 2-(1,3-dioxane), 2-(1,3-oxathiolane); dimethyl ketal and diethyl ketal;
R119 and R120 are each a member independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl substituted by 0 to 3 fluorine atoms;
R121 is a member independently selected from the group consisting essentially of fluoro and R120;
R122 is a member independently selected from the group consisting essentially of (C1-C6) alkyl; (C2-C3) alkenyl; (C3-C7) cycloalkyl; (C3-C7) cycloalkyl(C1-C2) alkyl; (C6-C10) aryl; and (C3-C9)heterocyclyl; where said aryl and heterocyclyl are as defined under RA5 above; and where said R122 groups are substituted with 0 to 3 substituents independently selected from the group consisting essentially of methyl; ethyl; mono-, di-, and tri-fluoromethyl; and bromo, chloro, or fluoro;
R123 is a member independently selected from the group consisting essentially of hydrogen and R122;
R124 is a member independently selected from the group consisting essentially of hydrogen and R125; or when R124 and R127 appear together as NR127R124 then R127 and R124 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring optionally containing one additional heteroatom selected from O, N and S;
R125 is a member independently selected from the group consisting essentially of (C1-C6) alkyl and xe2x80x94(CR119R120)nR126, where n is an integer selected from 0, 1, and 2 and R126 and said (C1-C6) alkyl are substituted by 0 to 3 substituents where each said substituent is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; cyano; NR120R127; C(xe2x95x90O)R119; OR119; C(xe2x95x90O)NR120R127; OC(xe2x95x90O)NR120R127; NR127C(xe2x95x90O)NR127R120; NR127C(xe2x95x90O)R120; NR17C(xe2x95x90O)O(C1-C4) alkyl; C(NR127)NR127R120; C(NCN)NR127R120; C(NCN)S(C1-C4) alkyl; NR127C(NCN)S(C1-C4) alkyl; NR127C(NCN)NR127R120; NR127S(xe2x95x90O)2(C1-C4)alkyl; S(O)n(C1-C4) alkyl; where n is an integer selected from 0, 1, and 2; NR127C(xe2x95x90O)C(xe2x95x90O)NR127R120, NR127C(xe2x95x90O)C(xe2x95x90O)R127; thiazolyl; imidazolyl; oxazolyl; pyrazolyl; triazolyl; tetrazolyl; and (C1-C2) alkyl substituted with 0 to 3 fluorine atoms;
R126 is a member independently selected from the group consisting essentially of (C3-C7) cycloalkyl; pyridyl; pyrimidyl; pyrazolyl; imidazolyl; triazolyl; pyrrolyl; piperazinyl; piperidinyl; morpholinyl; furanyl; thienyl; thiazolyl; quinolinyl; naphthyl; and phenyl;
R127 is a member independently selected from the group consisting essentially of OR119 and R121;
R128 is a member independently selected from the group consisting essentially of H; C(Y)R124; C(xe2x95x90O)OR2; C(Y)NR127R124; CN; C(NR127)NR127R124; C(NOR119)R124; C(xe2x95x90O)NR119NR119C(xe2x95x90O)R119; C(xe2x95x90O)NR119NR127R124; C(NOR124)R119; C(NR119)NR127R124; C(NR124)NR119R120; C(NCN)NR127R124; C(NCN)S(C1-C4) alkyl; CR119R120OR124; CR119R120SR124; CR119R120S(O)nR125, where n is an integer selected from 0, 1, and 2; CR119R120NR124R127; CR119R120NR127S(xe2x95x90O)2R125; CR119R120NR127C(Y)R124; CR119R120NR127C(xe2x95x90O)OR125; CR119R120NR127C(Y)NR127R124; CR119R120NR127C(NCN)NR127R124; CR119R120NR127C(CR9NO2)S(C1-C4) alkyl; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; wherein said recited heterocyclic groups are substituted by 0 to 3 substituents where each said substituent is independently selected from the group consisting essentially of R124;
R129 is a member independently selected from the group consisting essentially of xe2x80x94C(xe2x95x90O)R12; xe2x80x94C(xe2x95x90O)NR119R124; xe2x80x94S(xe2x95x90O)2R125; and xe2x80x94S(xe2x95x90O)2NR119R124;
Y is O or S; and,
Z is O; NR127; NCN; C(xe2x80x94CN)2; CR119CN; CR119NO2; CR119C(xe2x95x90O)OR119; CR119C(xe2x95x90O)NR119R120; C(xe2x80x94CN)C(xe2x95x90O)O(C1-C4) alkyl); and C(xe2x80x94CN)C(xe2x95x90O)NR119R120;
xe2x80x94OR, said substituents defining R2a and R2b comprise:
II
a member selected from the group consisting essentially of R229; xe2x80x94C(xe2x95x90O)NR222(CHR222)mC(xe2x95x90O)NR222(CH2)q(C6-C10) aryl); xe2x80x94C(xe2x95x90NR242)NH(CH2)p(C6-C10) aryl; xe2x80x94C(xe2x95x90O)NR218(CHR222)mC(xe2x95x90O)NR222(CH2)pOR222; xe2x80x94C(xe2x95x90O)NR222(CHR222)mS(C1-C4) alkyl; xe2x80x94C[xe2x95x90NOC(xe2x95x90O)R235]R236; xe2x80x94CR227R228CHR238NR219SO2(CH2)pA; xe2x80x94CR227R228CHR238NR219P(xe2x95x90O)(OR222)C(xe2x95x90O)(C1-C4) alkyl; xe2x80x94CR227R238CHR238NR219P(xe2x95x90O)[(C1-C4) alkoxy]2, -Z3-R217; and xe2x80x94(CR227R228)mNR219(C(O))qR220 wherein p is an integer selected from 0, 1, and 2; m is an integer selected from 1, 2, 3, 4, 5, and 6; and q is an integer selected from 1 and 2;
xe2x80x94OR, said substituents defining R2a and R2b comprise a moiety of partial Formulas (IIA) through (III), inclusive: 
wherein in said partial Formulas (IIA)-(III), the structures of partial Formulas (IIF) and (IIG) are attached to the nucleus of Formula (IA) or (IB) at carbons 5, 6, or 7 of said partial Formulas (IIF) and (IIG); the dashed line in partial Formulas (IIC) and (IID) indicates a single bond or double bond, except that R316 is absent in formulas (IIC) and (IIID) where said dashed line indicates a double bond; n is an integer selected from 0, 1, and 2; p is an integer selected from 0, 1, 2, 3, 4, 5, and 6; and m is an integer selected from 0, and 1;
R213 is a member independently selected from the group consisting essentially of xe2x80x94C(xe2x95x90O)N(CH3)(OCH3) and xe2x80x94(CH2)nOH, where n is an integer selected from 0, 1, 2, 3, and 4;
R214 and R215 are independently selected from the group consisting essentially of H; ethyl; xe2x80x94CO2H; and xe2x80x94C(xe2x95x90O)NHOH;
R216 is a member independently selected from the group consisting essentially of H; hydroxy; (C1-C6) alkyl; (C1-C6) alkoxy; xe2x80x94OC(xe2x95x90O)(C1-C6) alkyl and xe2x80x94OC(xe2x95x90O)(C6-C10) aryl;
R217 is a member independently selected from the group consisting essentially of (C6-C10)aryl and a 5- to 10-membered heterocyclyl, wherein said R217 groups are substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluroro; trifluoromethyl; cyano; nitro; xe2x80x94CO2R222, (C1-C4) alkoxy; xe2x80x94OC(xe2x95x90O)(C1-C4) alkyl; xe2x80x94NR222C(xe2x95x90O)(C1-C4)alkyl; xe2x80x94C(xe2x95x90O)NH2; xe2x80x94C(xe2x95x90O)NHOH; xe2x80x94C(xe2x95x90O)O(C1-C4) alkyl; (C1-C4) alkyl; xe2x80x94S(O)nR222 where n is an integer selected from 0, 1, and 2; benzoyl; xe2x80x94NR222R223, xe2x80x94OR222, (C1-C6) alkanoyl; xe2x80x94Y1xe2x80x94(C6-C10) aryl; xe2x80x94C(xe2x95x90O)O(C6-C10) aryl; xe2x80x94NH(C6-C10) aryl; xe2x80x94C(xe2x95x90O)NH(C6-C10) aryl; xe2x80x94C(xe2x95x90O)NR222O(CH2)n(C6-C10) aryl, where n is an integer select from 1, 2, and 3; and xe2x80x94SO2NH(C6-C10) aryl;
R218 is a member independently selected from the group consisting essentially of H; (C1-C6) alkyl; and xe2x80x94(CH2)n(C6-C10) aryl, where n is an integer selected from 0, 1, 2, 3, and 4;
R219 is a member independently selected from the group consisting essentially of H; xe2x80x94OR220; xe2x80x94(CH2)mA; and xe2x80x94CH2O(CH2)mA, where m is an integer selected from 0, 1, and 2
R220 is a member independently selected from the group consisting essentially of (C1-C4) alkyl; xe2x80x94OR222, xe2x80x94CR222R223OR222; xe2x80x94CR222R223NR222R223; xe2x80x94CR222(OR223)CR222R223OR222; 2,2-dimethyl-1,3-dioxolan-4-yl; xe2x80x94NR222C(xe2x95x90O)NR222R223, xe2x80x94S(CR222R223)nCH3 where n is an integer selected from 0, 1, 2, 3, 4, and 5; xe2x80x94NR222(CH2)q(pyridyl) where q is an integer selected from 0 and 1; xe2x80x94P(xe2x95x90O)[(C1-C4) alkoxy)]2; xe2x80x94NR222R223; xe2x80x94NR222OR223; xe2x80x94NR222NR223R221, xe2x80x94NR222CH2R224; xe2x80x94OCH2NR222C(xe2x95x90O)R224; xe2x80x94OCH2C(xe2x95x90O)NR225R226, xe2x80x94OCHR222OC(xe2x95x90O)(C1-C4) alkyl; xe2x80x94OCHR222C(xe2x95x90O)(C1-C3) alkoxy; xe2x80x94O(CH2)mR221; and xe2x80x94NR222(CH2)mR221 where m is an integer selected from 0, 1, and 2;
R221 is a member independently selected from the group consisting essentially of H and A;
each R222 and R223 is a member independently selected from the group consisting essentially of H and (C1-C4) alkyl;
R224 is a member independently selected from the group consisting essentially of methyl and phenyl;
R225 is a member independently selected from the group consisting essentially of H; methyl; ethyl; and xe2x80x94CH2CH2OH;
R226 is a member independently selected from the group consisting essentially of H; methyl; ethyl; xe2x80x94CH2C(xe2x95x90O)NH2; and xe2x80x94CH2CH2OH;
each R227 is a member independently selected from the group consisting essentially of H; hydroxy; cyano; halo; (C1-C3) alkyl; (C1-C3) alkoxy; xe2x80x94NR222R223; xe2x80x94C(xe2x95x90O)OR222; xe2x80x94C(xe2x95x90O)OR222; xe2x80x94C(xe2x95x90O)R222; xe2x80x94CHxe2x95x90CR222R223; xe2x80x94Cxe2x89xa1CR222; xe2x80x94CH2NR222R223; xe2x80x94CH2OR222; xe2x80x94C(xe2x95x90O)NR222R223; xe2x80x94C(Y5)H; and xe2x80x94CH2NR12C(xe2x95x90O)C(xe2x95x90O)NR222R223; provided that when R227 is hydroxy then R228 is H or (C1-C4) alkyl;
each R228 is a member independently selected from the group consisting essentially of H; fluoro; cyano; and (C1-C4) alkyl; where said methyl is substituted by 0 to 3 substituents each comprising a fluorine atom;
or R227 and R228 are taken together to form an oxo (xe2x95x90O) moiety;
R229 is a member independently selected from the group consisting essentially of phenyl; naphthyl; pyrrolyl; furanyl; thienyl; oxazolyl; pyridinyl; pyrimidinyl; pyridazinyl; quinolinyl; isoquinolinyl; 5,6,7,8-tetrahydroquinolinyl; and 5,6,7,8tetrahydroisoquinolinyl, where said R229 groups, except said phenyl, are substituted by 0 to 3 substituents R233, and wherein said phenyl R229 group is substituted by 0 to 3 substituents independently selected from R233 and R234;
R230 is a member independently selected from the group consisting essentially of xe2x80x94C(xe2x95x90O)R231; xe2x80x94C(xe2x95x90O)C(xe2x95x90O)R231, xe2x80x94C(xe2x95x90O)C(Y2)C(xe2x95x90O)R231and a moiety of partial Formula (IIJ): 
wherein
R231 is a member independently selected from the group consisting essentially of H; xe2x80x94OR232; xe2x80x94NHR232, xe2x80x94NHOH; xe2x80x94NHNH2; xe2x80x94(CH2)nY3(phenyl) and xe2x80x94(CH2)nY3(pyridyl) where n is an integer selected from 0, 1, 2, 3, and 4;
R232 is a member independently selected from the group consisting essentially of H; (C1-C8) alkyl; xe2x80x94(CH2)nY3(phenyl) and xe2x80x94(CH2)nY3(pyridyl) where n is an integer selected from 0, 1, 2, 3, and 4;
each R233 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; (C1-C6) alkyl; (C1-C7)alkoxy; (C2-C6) alkylenedioxy; trifluoromethyl; xe2x80x94NR222R223; nitro; xe2x80x94C(NR222)NR222R223; xe2x80x94C(xe2x95x90O)NR222R223C(xe2x95x90O)R222; xe2x80x94C(NOR222)R223; xe2x80x94C(NCN)NR222R223; xe2x80x94C(NCN)SR222; xe2x80x94(CH2)m(CN) where m is an integer selected from 0, 1, 2, and 3; hydroxy; xe2x80x94C(xe2x95x90O)R222, xe2x80x94C(xe2x95x90O)NR222OR223; xe2x80x94C(xe2x95x90O)NR222NR222R223; xe2x80x94OC(xe2x95x90O)NR222R223; xe2x80x94NR222C(xe2x95x90O)R222; xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NR222R223; xe2x80x94CO2R222; xe2x80x94SO2R222; xe2x80x94SO2NR222R222; xe2x80x94C(xe2x95x90O)NR222R223; xe2x80x94NR222SO2R223; and xe2x80x94NR222C(xe2x95x90O)NR222R223;
each R234 is a member independently selected from the group consisting essentially of imidazolyl; pyrazolyl; triazolyl; tetrazolyl; oxazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; thiazolyl; oxazolidinyl; thiazolidinyl; and imidazolidinyl, where each of said foregoing R234 substituents is substituted by 0 to 3 substituents R233;
R235is a member independently selected from the group consisting essentially of xe2x80x94NR222R223; xe2x80x94NH(C6-C10) aryl; (C1-C6) alkoxy; and (C6-C10) aryloxy;
R236 is a member independently selected from the group consisting essentially of H; (C1-C6) alkyl and xe2x80x94(CH2)mY4(phenyl) where m is an integer selected from 0, 1, 2, 3, and 4 and the phenyl moiety of said xe2x80x94(CH2)mY4(phenyl)R236 group is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; xe2x80x94OR222; (C1-C6) alkanoyloxy; (C6-C10)aryloxy; xe2x80x94NR222R223; xe2x80x94NH(C6-C10)aryl; and xe2x80x94NHC(xe2x95x90O)(C1-C4) alkyl;
each R237 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; xe2x80x94(CH2)pNR222C(xe2x95x90O)CH3 where p is an integer selected from 1, 2, 3, 4, and; (C1-C4) alkoxy; nitro; cyano; xe2x80x94NR222R223; xe2x80x94COR222; xe2x80x94OR222, xe2x80x94C(Y1)NR222R223; xe2x80x94NR222C(NCN)S(C1-C3) alkyl; xe2x80x94NR222C(NCN)NR222R223; xe2x80x94NR222C(xe2x95x90O)NR222R223; xe2x80x94NR222C(xe2x95x90O)C(xe2x95x90O)NR222R223; xe2x80x94C(xe2x95x90NR222)NR222R223; xe2x80x94S(O)mCH3 where m is an integer selected from 0, 1, and 2, xe2x80x94C(xe2x95x90NR222)S(C1-C3) alkyl; xe2x80x94NR222SO2(C1-C3) alkyl; xe2x80x94OC(xe2x95x90O)R222; xe2x80x94OC(xe2x95x90O)NR222R223; xe2x80x94NR222SO2CF3; xe2x80x94NR222C(xe2x95x90O)C(xe2x95x90O)OR222; xe2x80x94NR222C(xe2x95x90O)R222; xe2x80x94NR222C(xe2x95x90O)OR222; imidazolyl; thiazolyl; oxazolyl; pyrazolyl; triazolyl; and tetrazolyl;
R238 is a member independently selected from the group consisting essentially of H; fluoro; cyano; and (C1-C2) alkyl, where said alkyl is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; xe2x80x94C(xe2x95x90O)NR222R223; and xe2x80x94C(xe2x95x90O)OR222;
R239 is a member independently selected from the group consisting essentially of phenyl substituted by 0 to 2 substituents independently selected from xe2x80x94NR222R223, nitro, halo, xe2x80x94OR222, xe2x80x94NHR240, xe2x80x94N240R241, and xe2x80x94C(xe2x95x90O)OR222;
each R240 and R241 is a member independently selected from the group consisting essentially of (C1-C8) alkyl and (C2-C8) alkenyl;
R242 is pyridin-4-yl substituted by 0 to 2 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; and (C1-C4) alkyl;
each A is a member independently selected from the group consisting essentially of (C1-C6) alkyl; pyridyl; morpholinyl; piperidinyl; imidazolyl; thienyl; pyrimidyl; thiazolyl; triazolyl; quinolinyl; phenyl; and naphthyl; wherein the foregoing A groups are substituted with 0 to 3 substituents R237; or A is xe2x80x94(CH2)qS(C1-C4)alkyl wherein q is an integer selected from 1 and 2;
W is a member independently selected from the group consisting essentially of O; NOH; NNH2; NOC(xe2x95x90O)CH3; and NNHC(xe2x95x90O)CH3;
Y is O or S;
Y2 is O, NOH or H2;
Y3 is a bond or xe2x80x94CHxe2x95x90CHxe2x80x94;
Y4 is a bond, O, S, or xe2x80x94NHxe2x80x94;
Y5 is a member independently selected from the group consisting essentially of O; NR222; NOR222; NCN; C(CN)2; CR222NO2; CR222C(xe2x95x90O)OR222; CR222C(xe2x95x90O)NR222R223; C(CN)NO2; C(CN)C(xe2x95x90O)OR222; and C(CN)C(xe2x95x90O)NR222R223; and
Z3 is a member independently selected from the group consisting essentially of xe2x80x94NR222; xe2x80x94(CH2)mxe2x80x94; xe2x80x94CH2C(xe2x95x90O)NHxe2x80x94; xe2x80x94NHCH2C(xe2x95x90O)xe2x80x94; xe2x80x94CH2C(Y1)CH2xe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH(Y1H)xe2x80x94; xe2x80x94C(Y1)xe2x80x94; xe2x80x94CH2C(Y1); xe2x80x94C(Y1)CH2xe2x80x94; xe2x80x94C(Y1)C(Y1)-; xe2x80x94CH2NR222-; xe2x80x94CH2-Y1; xe2x80x94C(Y1)NR218(CHR222)nxe2x80x94; xe2x80x94NR218C(Y1)(CHR222)nxe2x80x94; xe2x80x94NHCH2xe2x80x94; -Y1-CH2xe2x80x94; xe2x80x94SOCH2xe2x80x94; xe2x80x94CH2SOxe2x80x94; xe2x80x94SO2CH2xe2x80x94; xe2x80x94CH2SO2xe2x80x94; xe2x80x94OC(Y1)-; xe2x80x94Nxe2x95x90Nxe2x80x94; xe2x80x94NHSO2xe2x80x94; xe2x80x94SO2NHxe2x80x94; xe2x80x94C(Y1)C(Y1)NHxe2x80x94; xe2x80x94NHC(xe2x95x90O)Oxe2x80x94; xe2x80x94OC(xe2x95x90O)NHxe2x80x94; and xe2x80x94NHC(xe2x95x90O)NHxe2x80x94; wherein for said Z3 moieties n is an integer selected from 0, 1, 2, 3, and 4; and m is an integer selected from 1, 2, and 3;
xe2x80x94OR said substituents defining R2a and R2b comprise:
III
a member independently selected from the group consisting essentially of 2-oxo-4-pyrrolyl; pyrazolyl; 2-oxo-3,4-dihydro-5-pyrimidyl; 2-oxo-3,4-dihydro-4-pyrimidyl; 2-oxo-tetrahydro-4-pyrimidyl; 2-oxo-tetrahyro-5-pyrimidyl; 2-oxo-4-pyrimidyl; and 2-oxo-5-pyrimidyl; wherein each of said R2a and R2b groups is substituted by 0, 1, 2, 3, or 4 R236 groups;
xe2x80x94OR, said substituents defining R2a and R2b comprise a moiety of partial Formulas (IIA) through (III), inclusive: 
wherein, in said partial Formulas (IIIA)-(IIIT), q is an integer selected from 0 and 1 in partial Formula (IIIB); n is an integer selected from 0, 1, and 2 in partial Formula (IIIC); and the dashed lines appearing in formulas (IIIB), (IIID), (IIIG), (IIIH), (IIII), (IIIJ) and (IIIO ) represent a double bond or a single bond;
X1 is O or S;
X2, in formula (IIIK) and where the dashed line in formula (IIIJ) represents a double bond, is a member independently selected from the group consisting essentially of CR335; CR336; CR346; and COC(xe2x95x90O)NR339R342; or, where the dashed line in formula (IIIJ) represents a single bond, X2 is a member independently selected from the group consisting essentially of CR335R339; CR336R339; and CR346R339;
X3 is a member independently selected from the group consisting essentially of C(xe2x95x90Z3); C(S); and CR336R340;
X4 is a member independently selected from the group consisting essentially of xe2x80x94(CH2)m- where m is an integer selected from 0, 1, and 2;
X5 is a bond or xe2x80x94CH2xe2x80x94;
X6 is a member independently selected from the group consisting essentially of xe2x80x94CH2xe2x80x94 and xe2x80x94C(xe2x95x90O)xe2x80x94;
R333 is a member independently selected from the group consisting essentially of H; hydroxy; (C1-C4)alkoxy; xe2x80x94CHR337(O)q(CH2)mA where q is an integer selected from 0 and 1, is an integer selected from 0, 1, and 2;
R334 is a member independently selected from the group consisting essentially of H; hydroxy; (C1-C4) alkyl; (C1-C2) alkoxy; xe2x80x94OC(xe2x95x90O)CH3; (C2-C3) alkenyl; and phenyl(C1-C2) alkyl-;
R335 is a member independently selected from the group consisting essentially of H; hydroxy; xe2x80x94(CH2)mA where m is an integer selected from 0, 1, and 2; (C1-C6) alkyl; and (C2-C3) alkanoyl; where said alkyl group is substituted by 0 to 3 subtituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; xe2x80x94NR340R341; xe2x80x94CO2R340; xe2x80x94OR340; xe2x80x94OC(xe2x95x90O)R340; xe2x80x94C(xe2x95x90O)R340; cyano; xe2x80x94C(xe2x95x90Y)NR340R341; xe2x80x94NR340C(xe2x95x90Y)NR340R341, xe2x80x94NR340C(xe2x95x90Y)R340; xe2x80x94NR340C(xe2x95x90O)OR340); xe2x80x94C(NR340)NR340R341; xe2x80x94C(NCN)NR340R341; xe2x80x94C(NCN)SR340; xe2x80x94NR340SO2R340; xe2x80x94S(O)mR340, where m is an integer selected from 0, 1, and 2; xe2x80x94NR340SO2CF3; xe2x80x94NR340C(xe2x95x90O)C(xe2x95x90O)NR340R341; xe2x80x94NR340C(xe2x95x90O)C(xe2x95x90O)OR340; imidazolyl; and 1-(NHR340)-2-imidazolyl;
each R336 is a member independently selected from the group consisting essentially of H; bromo, chloro, or fluoro; cyano; R33; cyclopropyl substituted by 0 or 1 substituent independently selected from the group consisting essentially of R339; xe2x80x94OR340; xe2x80x94CH2OR340; xe2x80x94NR340R342; xe2x80x94CH2NR340R342; xe2x80x94C(xe2x95x90O)OR340; xe2x80x94C(xe2x95x90O)NR340R342; xe2x80x94CHxe2x95x90CR339R339; xe2x80x94Cxe2x89xa1CR339; and xe2x80x94C(xe2x95x90Z3)H;
R337 is a member independently selected from the group consisting essentially of H; xe2x80x94C(xe2x95x90O)R338; imidazolyl; pyrazolyl; triazolyl; tetrazolyl; oxazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; thiazolyl; oxazolidinyl; thiazolidinyl; and imidazolidinyl;
each R338 is a member independently selected from the group consisting essentially of xe2x80x94OR340; xe2x80x94NR R342; and xe2x80x94R343;
each R339 is a member independently selected from the group consisting essentially of H; bromo, chloro, or fluoro; and (C1-C4) alkyl substituted by 0 to 3 fluorine atoms;
each R340 and R341 is a member independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl;
each R342 is a member independently selected from the group consisting essentially of xe2x80x94OR340 and xe2x80x94R340;
R343 is (C1-C4) alkyl;
each R343 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; cyano; xe2x80x94NR340R346; xe2x80x94NR346R342; xe2x80x94C(xe2x95x90Z3)R338; xe2x80x94S(O)mR343 where m is an integer selected from 0, 1, and 2; xe2x80x94OR342; xe2x80x94OC(xe2x95x90O)NR340R342; xe2x80x94C(NR342)NR340R342; xe2x80x94C(NR340)SR343; xe2x80x94OC(xe2x95x90O)CH3; xe2x80x94C(NCN)NR340R342; xe2x80x94C(S)NR340R342; xe2x80x94NR342C(xe2x95x90O)R347; xe2x80x94C(xe2x95x90O)R347; oxazolyl; imidazolyl; thiazolyl; pyrazolyl; triazolyl; and tetrazolyl;
each R345 is a member independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl substituted by 01 to 3 fluorine atoms;
each R346 is a member independently selected from the group consisting essentially of H; xe2x80x94R343; xe2x80x94C(xe2x95x90O)R343; xe2x80x94C(xe2x95x90O)C(xe2x95x90O)R338; xe2x80x94C(xe2x95x90O)NR340R342; xe2x80x94S(O)mR343 where m is an integer selected from 0, 1, and 2; xe2x80x94C(NCN)SR343; xe2x80x94C(NCN)R343; xe2x80x94C(NR342)R343; xe2x80x94C(NR342)SR343; and xe2x80x94C(NCN)NR340R342;
each R347 is a member independently selected from the group consisting essentially of xe2x80x94R343; xe2x80x94C(xe2x95x90O)R343; oxazolidinyl; oxazolyl; thiazolyl; pyrazolyl; triazolyl; tetrazolyl; imidazolyl; imidazolidinyl; thiazolidinyl; isoxazolyl; oxadiazolyl; thiadiazolyl; morpholinyl; piperidinyl; piperazinyl; and pyrrolyl; where each of said recited R347 heterocyclic groups is substituted by 0 to 2 (C1-C2) alkyl groups;
R348 is a member independently selected from the group consisting essentially of H; (C1-C5) alkyl; (C2-C5) alkenyl; benzyl; and phenethyl;
R349 is a member independently selected from the group consisting essentially of H; (C1-C5) alkyl; (C1-C5) alkanoyl; and benzoyl;
R350 is a member independently selected from the group consisting essentially of H; (C1-C4) alkyl; carboxy; aminocarbonyl; (C1-C6) alkyl substituted by 0 or 1 carboxy, xe2x80x94(CH2)mC(xe2x95x90O)(C1-C6) alkoxy; or xe2x80x94(CH2)m(C6-C10) aryl; where m is an integer selected from by 0 or 1, and 2;
R351 is a member independently selected from the group consisting essentially of H; (C1-C6) alkyl; xe2x80x94C(xe2x95x90Y)R352; xe2x80x94C(xe2x95x90Y)NH352; xe2x80x94C(xe2x95x90O)OR352; and xe2x80x94(CH2)nX7(pyridyl) where n is an integer selected from 0, 1, 2, 3, 4, and to 5; and X7 is a bond or xe2x80x94CHxe2x95x90CHxe2x80x94; and where said pyridyl moiety is substituted by 0 or 1 bromo, chloro, or fluoro;
R352 is a member independently selected from the group consisting essentially of (C1-C6) alkyl (C3-C8) cycloalkyl; xe2x80x94(CH2)m(C6-C10) aryl; and xe2x80x94(CH2)nX7(pyridyl) where n is an integer selected from 0, 1, 2, 3, 4, and 5; and X7 is a bond or xe2x80x94CHxe2x95x90CHxe2x80x94; and where said pyridyl moiety is substituted by 0 or 1 bromo, chloro, or fluoro;
R353 is a member independently selected from the group consisting essentially of H; xe2x80x94R345; (C1-C3) alkyl substituted by 0 or 1 substituent hydroxy, or (C1-C3) alkyoxy(C1-C3) alkyl;
R354 is a member independently selected from the group consisting essentially of H; xe2x80x94R345; carboxy; (C1-C3) alkyoxy(C1-C3) alkyl-; (C3-C7) cycloalkyl; and (C1-C5) alkyl substituted by 0 or 1 xe2x80x94NR340R341;
or R353 and R354 are taken together to form xe2x80x94CH2OCH2OCH2xe2x80x94;
R355 is a member independently selected from the group consisting essentially of H; hydroxy; (C1-C4) alkyl substituted by 0 or 1 substituent comprising a member independently selected from the group consisting essentially of hydroxy; xe2x80x94C(xe2x95x90O)R340; xe2x80x94NR340R341; xe2x80x94(CH2)mNHC(xe2x95x90O)R340; xe2x80x94(CH2)mNHC(xe2x95x90O)R; xe2x80x94(CH2)mCO2R340; xe2x80x94(CH2NHC(xe2x95x90O)R341; xe2x80x94(CH2)mC(xe2x95x90O)N(OH)R340; xe2x80x94(CH2)mSO2NR340R341; xe2x80x94(CH2)mPO3H2; xe2x80x94(CH2)mSO2NHC(xe2x95x90O)R343; and xe2x80x94(CH2)mSO2NHC(xe2x95x90O)(phenyl), where m is an integer selected from 0, 1, 2, 3, and 4;
R353 is a member independently selected from the group consisting essentially of H; (C1-C4) alkyl; phenyl; xe2x80x94NR340R341; and xe2x80x94NR340(C1-C4) alkanoyl;
R357 is a member independently selected from the group consisting essentially of xe2x80x94R340; xe2x80x94CH2CO2R343; and xe2x80x94CH2C(xe2x95x90O)NR340R341;
R358 is a member independently selected from the group consisting essentially of xe2x80x94C(xe2x95x90O)R340; xe2x80x94C(xe2x95x90O)(C6-C10) aryl; xe2x80x94C(xe2x95x90O)(C3-C9) heteroaryl; xe2x80x94CO2R340; xe2x80x94C(xe2x95x90O)NR340R341; cyano; nitro; xe2x80x94CH2OH; xe2x80x94NR340SO2R340; xe2x80x94NHSO2(C6-C10) aryl; xe2x80x94NHCO2(C1-C4) alkyl; xe2x80x94NR340C(xe2x95x90O)R340; and xe2x80x94NHCO2(C6-C10) aryl;
R359 is a member independently selected from the group consisting essentially of xe2x80x94R345; cyano; carboxy; formyl; xe2x80x94C(xe2x95x90O)R340; and (C1-C4) alkanoyl;
R360 is a member independently selected from the group consisting essentially of cyano; xe2x80x94NR340R341; xe2x80x94SO2(C1-C4) alkyl; xe2x80x94SO2(C6-C10) aryl; xe2x80x94C(xe2x95x90O)R340; xe2x80x94C(xe2x95x90O)(C6-C10) aryl; xe2x80x94C(xe2x95x90O)(C3-C9) heteroaryl; xe2x80x94C(xe2x95x90O)NR340R341; and xe2x80x94CO2R340;
R361 and R362 is each a member independently selected from the group consisting essentially of H; cyano; nitro; xe2x80x94CO2R340; xe2x80x94C(xe2x95x90O)NR340R341; xe2x80x94CH2OH; xe2x80x94C(xe2x95x90O)R340; xe2x80x94NHCO2R340; and xe2x80x94NHSO2R3;
A is a member independently selected from the group consisting essentially of pyridyl; morpholinyl; piperidinyl; imidazolyl; thienyl; pyrimidyl; thiazolyl; phenyl; and naphthyl; where each of said A groups is substituted by 0 to 2 substituents R344 or by 1 substituent R345;
Z3 is a member independently selected from the group consisting essentially of O; xe2x80x94NR342; NOR340; N(CN); C(CN)2; CR340NO2; CR340C(xe2x95x90O)OR343; CR340 C(xe2x95x90O)NR340R341; C(CN)NO2; C(CN)C(xe2x95x90O)OR343; and C(CN)C(xe2x95x90O)NR340R341; and,
Y is O or S;
xe2x80x94OR said substituents defining R2a and R2b comprise a moiety of partial Formula (IV):
IV 
wherein
the broken line indicates a single or double bond;
X1 is xe2x80x94CR472R473xe2x80x94 where said broken line indicates a single bond; or xe2x80x94CR473xe2x80x94 where said broken line indicates a double bond;
X2 is xe2x80x94OR475R477R478xe2x80x94 or xe2x80x94C(xe2x95x90NOR481)R482xe2x80x94 where said broken line indicates a single bond; or xe2x80x94CR477R478 where said broken line indicates a double bond;
R472 is a member independently selected from the group consisting essentially of H; hydroxy; bromo, chloro, or fluoro; and xe2x80x94OR479;
each R473 is a member independently selected from the group consisting essentially of cyano; cyanomethyl; benzyloxy; xe2x80x94R475; xe2x80x94CO2R475; xe2x80x94CO2(CH2)n(C6-C10) aryl; xe2x80x94C(Y)NR475R476; xe2x80x94C(Y)NR475(CH2)n(C6-C10) aryl; xe2x80x94(CH2)n(C6-C10) aryl; and xe2x80x94(CH2)n(5- to 10-membered heteroaryl); where n is an integer selected from 0, 1, 2, and 3; each R473 group is substituted by 0 to 3 substituents R474; and each R473 group is substituted by 0 or 1 substituent R480;
each R474 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; cyano; nitro; (C1-C6) alkyl; (C2-C6) alkenyl; xe2x80x94OR475; (C3-C7)cycloalkoxy; xe2x80x94NR475R476; xe2x80x94NR475OR476; xe2x80x94S(O)mR475 where m is an integer selected from 0, 1, and 2; xe2x80x94CO2R475, xe2x80x94C(xe2x95x90O)R475; xe2x80x94SO2NR475R476; xe2x80x94C(xe2x95x90O)NR475NR476; xe2x80x94CR475R476SO2NR475R476; xe2x80x94CR475R476C(xe2x95x90O)NR475R476; xe2x80x94NHSO2R475; xe2x80x94NHSO2NR475R476; xe2x80x94NHC(xe2x95x90O)NR476; xe2x80x94NHC(xe2x95x90O)(C1-C6) alkyl; and xe2x80x94NHC(xe2x95x90O)O(C1-C6) alkyl);
each R475 and R476 is a member independently selected from the group consisting essentially of H; and (C1-C6) alkyl;
R477 is a member independently selected from the group consisting essentially of xe2x80x94R473; 2-oxo-pyridyl; 3-oxo-pyridyl; 4-oxo-pyridyl; 2-oxo-pyrrolyl; 4-oxo-thiazolyl; 4-oxo-piperidyl; 2-oxo-quinolyl; 4-oxo-quinolyl; 1-oxo-isoquinolyl; 4-oxo-oxazolyl; 5-oxo-pyrazolyl; 5-oxo-isoxazolyl; and 4-oxo-isoxazolyl; where each of said R477 groups is substituted by 0 to 3 substituents R474;
R478 is a member independently selected from the group consisting essentially of xe2x80x94R475; cyano; xe2x80x94(CH2)p(C6-C10) aryl; and xe2x80x94(CH2)p(5- to 10-membered heteroaryl); where p is an integer selected from 1, 2, and 3; and where each said R478 group is substituted by 0 to 3 substituents R474;
R479 is a member independently selected from the group consisting essentially of formyl; carbamoyl; thiocarbamyl; (C1-C6) alkyl; (C2-C6) alkenyl; (C1-C4) alkoxy(C1-C4) alkyl-; and (C1-C6) alkanoyl; where said alkyl moieties of each of said R479 groups is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; and (C1-C4) alkoxy;
R480 is a member independently selected from the group consisting essentially of cyclobutyl; cyclopentyl; cyclohexyl; 2-cyclobuten-1-yl; 2-cyclopenten-1-yl; 3-cyclopenten-1-yl; 2,4-cyclopentadien-1-yl; 3,5-cyclohexadien-1-yl; pyrrolyl; pyrrolidinyl; dioxolanyl; imidazolyl; oxazolyl; imidazolidinyl; pyrazolyl; pyrazolidinyl; pyranyl; piperidinyl; 1,4-dioxanyl; morpholinyl; 1,4-dithianyl; thiomorpholinyl; piperazinyl; 1,3,5-trithianyl; oxazinyl; isoxazinyl; oxathiazinyl; and oxadiazinyl; where each of said R480 groups is substituted by 0 to 2 (C1-C2) alkyl;
R481 is a member independently selected from the group consisting essentially of H; (C1-6) alkyl; (C2-C6) alkenyl; (C2-C6) alkynyl; xe2x80x94C(Y)NR475R476; xe2x80x94C(Y)NH(C6-C10) aryl; xe2x80x94C(Y)(C1-C6) alkoxy; xe2x80x94C(Y)(C6-C10) aryloxy; and xe2x80x94C(Y)(C1-C6) alkyl);
R482 is a member independently selected from the group consisting essentially of phenyl and pyridinyl; where each of said R482 groups is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; (C1-C4) alkyl; hydroxy; (C1-C4) alkoxy; xe2x80x94NR475R476; and xe2x80x94S(O)mR475, where m is an integer selected from 0, 1, and 2; and,
Y is O or S;
xe2x80x94OR, said substituents defining R2a and R2b comprise a moiety of partial Formulas (VA) through (VM), inclusive:
V 
Preferred compounds of Formula (IA) or (IB) where R2a and R2b are as defined under (-IV-) above, include those wherein R1 is ethyl and R is cyclopentyl, cyclohexyl, or (C6-C10)aryl.
Other preferred compounds of Formula (IA) or (IB) include those wherein R473 is xe2x80x94(CH2)n(C6-C10) aryl or xe2x80x94(CH2)n(5- to 10-membered heteroaryl), where n is an integer selected from 0, 1, 2, and 3; and, more preferably, wherein R473 is phenyl or pyridin-4-yl.
Specific embodiments of the compounds of Formula (IA) or (IB) where R2a and R2b are as defined under (-I-) include those wherein R is cyclopentyl or cyclohexyl, R1 is (C1-C2) alkyl, preferably ethyl, one of R2a and R2b is hydrogen and the other is a substituent of Formula (IC) where the dashed line represents a single bond, m is 0, R113 and R114 are in a cis relationship to each other, R113 is cyano, R115 is hydrogen, and R114 is carboxy, xe2x80x94CH2OH, or xe2x80x94CH2C(xe2x95x90O)NH2.
Other specific embodiments of the compounds of Formula (IA) or (IB) include those wherein R is phenyl substituted by fluoro, R1 is (C1-C2) alkyl, preferably ethyl, one of R2a and R2b is hydrogen and the other is a substituent of Formula (IC) where the dashed line represents a single bond, R113 is cyano, and R115 and R114 are both hydrogen.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, means saturated monovalent hydrocarbon radicals which are straight or branched moieties containing from one to six, preferably one to four, carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, means O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, means unsaturated alkyl groups having one or more double bonds wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, unless otherwise indicated, means saturated monovalent cyclo hydrocarbon radicals containing from three to seven carbon atoms, preferably five or six carbon atoms, including such specific radicals as cyclobutyl, cyclopentyl and cycloheptyl.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, means an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, comprising a carbocyclic moiety which is a member independently selected from the group consisting essentially of benzyl; cis- and trans-decahydronaphthalenyl; 2,3-1H-dihydroindenyl (indanyl); indenyl; 1-naphthalenyl; 2-naphthalenyl; phenyl; and 1,2,3,4-tetrahydronaphthalenyl; and preferably means phenyl.
The term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d, as used herein, unless otherwise indicated, means aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N. Included within this meaning are heterocyclic groups which are benzo-fused ring systems and ring systems substituted with an oxo moiety. Included within the scope of this definition are the following specific groups: acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl.
With reference to the R114 substituent of partial Formula (IC) of Formula (IA) or (IB), the (C3-C9)heterocyclic group can be attached to the (C1-C6) alkyl group by a nitrogen or, preferably, a carbon atom. An example of a C3 heterocyclic group is thiazolyl, and an example of a C9 heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl. Examples of aromatic heterocyclic groups which are preferred are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl. A preferred heterocyclic group having a fused benzene ring is benzimidazolyl.
Where heterocyclic groups are specifically recited or covered as substituents for the compound of Formula (IA) or (IB) under (-I-), it is understood that all suitable isomers of such heterocyclic groups are intended. Thus, for example, in the definition of the substituent R114, the term xe2x80x9cthiazolylxe2x80x9d includes 2-, 4- or 5-thiazolyl; the term xe2x80x9cimidazolylxe2x80x9d includes 2-, 4- or 5-inidazolyl; the term xe2x80x9cpyrazolylxe2x80x9d includes 3-, 4- or 5-pyrazolyl; the term xe2x80x9coxazolylxe2x80x9d includes 2-, 4- or 5-oxazolyl; the term xe2x80x9cisoxazolylxe2x80x9d includes 3-, 4- or 5-isoxazolyl, and so on. Likewise, in the definition of substituent R116, the term xe2x80x9cpyridylxe2x80x9d includes 2-, 3- or 4-pyridyl.
Certain xe2x80x9caminalxe2x80x9d or xe2x80x9cacetalxe2x80x9d-like chemical structures within the scope of Formula (IA) or (IB) may be unstable. Such structures may occur where two heteroatoms are attached to the same carbon atom. For example, where R is (C1-C6) alkyl substituted by hydroxy, it is possible that the hydroxy may be attached to the same carbon that is attached to the nitrogen atom from which R extends. It is to be understood that such unstable compounds are not within the scope of the present invention.
Preferred compounds of Formula (IA) or (IB) under (-I-) include those wherein R2a or R2b is a group of the partial Formula (ICa) or (ICb): 
where for partial Formula (ICa) R113 and R114, especially where R114 is xe2x80x94OH, are cis with respect to each other; and for partial Formula (ICb) R116a, R116b, R116c, and R116d are independently selected from the group consisting essentially of xe2x80x94H; xe2x80x94CH3; xe2x80x94CF3; xe2x80x94CHF2; xe2x80x94CH2F; ethyl, i-propyl; and t-butyl;
Other preferred compounds of Formula (IA) or (IB) under (-I-) include those wherein R is a member independently selected from the group consisting essentially of cyclohexyl, cyclopentyl, cyclobutyl, methylenecyclopropyl, isopropyl, phenyl, and 4-fluoro-phenyl.
Other preferred compounds of Formula (IA) or (IB) under (-I-) include those wherein R1 is (C1-C2) alkyl substituted by 0 to 3 fluorine atoms, and, more preferably, those wherein R1 is ethyl.
Other preferred compounds of Formula (IA) or (IB) under (-I-) include those wherein one of R2a and R2b is hydrogen and the other is a group of partial Formula (IC) wherein the dashed line attached to the ring carbon atom to which R113 is attached represents a single bond.
Other preferred compounds of Formula (IA) or (IB) under (-I-) include those wherein one of R2a and R2b is hydrogen and the other is a group of partial Formula (IC) wherein the dashed line attached to the ring carbon atom to which R113 is attached represents a single bond and R113 is cyano.
Other preferred compounds of Formula (IA) or (IB) under (-I-) include those wherein one of R2a and R2b is hydrogen and the other is a group of partial Formula (IC) wherein the dashed line attached to the ring carbon atom to which R113 is attached represents a single bond, m is 0 and R115 is hydrogen.
Other preferred compounds of Formula (IA) or (IB) under (-I-) include those wherein one of R2a and R2b is hydrogen and the other is a group of partial Formula (IC) wherein the dashed line attached to the ring carbon atom to which R113 is attached represents a single bond; m is 0; R115 is hydrogen; and R114 is a member independently selected from the group consisting essentially of xe2x80x94H; xe2x80x94CH2OH; xe2x80x94C(CH3)2OH; xe2x80x94C(xe2x95x90O)OH; xe2x80x94C(xe2x95x90O)OCH3; xe2x80x94C(xe2x95x90O)OCH2CH3; and xe2x80x94CH2C(xe2x95x90O)NH2.
Other more preferred compounds of Formula (IA) or (IB) under (-I-) include those wherein R is a member independently selected from the group consisting essentially of cyclobutyl, cyclopentyl, cyclohexyl, and 4-fluoro-phenyl; R1 is ethyl; one of R2a and R2b is hydrogen and the other is a group of partial Formula (ICb); R113 is cyano; R115 is hydrogen; R114 is xe2x80x94OH, and R113 and R114 are cis with respect to each other; and R116a, R116b, R116c, and R116d are each a member independently selected from the group consisting essentially of xe2x80x94H; and xe2x80x94CH3;
Preferred compounds of Formula (IA) or (IB) include those wherein R1 is ethyl.
Other preferred compounds of Formula (IA) or (IB) include those wherein R is a member independently selected from the group consisting essentially of cyclohexyl; cyclopentyl; methylenecyclopropyl; isopropyl; phenyl; and 4-fluoro-phenyl.
Specific preferred compounds of Formula (IA) or (IB) under (-I-) include:
1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;
Trans-4-cyano4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;
Cis-4-cyano4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;
Trans-4-cyano4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
Cis-4-cyano4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
1-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;
Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol6-yl)cyclohexanecarboxylic acid methyl ester;
Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;
Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
Cis-1-(1-cyclohexyl-3-ethyl-1H-indazole-6-yl)-4-hydroxymethylcyclohexanecarbonitrile;
Cis-4-cyano4-(1-cyclohexyl-3-ethyl-1H-indazol4-yl)cyclohexanecarboxylic acid amide;
Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid amide;
Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol6-yl)-4-(1-hydroxy-1-methylethyl)cyclohexanecarbonitrile;
Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;
Cis-1-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarbonitrile;
Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;
Cis-1-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;
Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol6-yl)-4-hydroxy4-methylcyclohexanecarbonitrile;
Trans-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy4-methylcyclohexanecarbonitrile;
Cis-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
Trans-4-cyano4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
6-Bromo-3-ethyl-1-(4-fluorophenyl)-1H-indazole;
4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarboxylic acid ethyl ester;
4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylic acid ethyl ester;
4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)cyclohex-3-enecarboxylic acid ethyl ester;
4-Cyano4-(1-cyclohexyl-3-ethyl-1H-indazol6-yl)-cyclohexanecarboxylic acid ethyl ester;
Cis-4-Cyano-4-3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)cyclohexanecarboxylic acid;
4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid; and
4-(1-Cyclohexyl-3-ethyl-1H-indazol6-yl)-4-hydroxycyclohexanecarboxylic acid.
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of Formula (IA) or (IB). For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylic acid groups and hydrochloride salts of amino groups. Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
Certain species of abovedesecribed compounds may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of Formula (IA) or (IB), and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of Formula (IA) or (IB), the invention includes the use of a racemate, a single enantiomeric form, a single diastereomeric form, or mixtures thereof. The compounds of Formula (IA) or (IB) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The present invention further relates to a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in a mammal comprising a pharmaceutically effective amount of a compound according to the above-described compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention further relates to a method for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) by administering to a patient an effective amount of a compound according to the above-described compounds or a pharmaceutically acceptable salt thereof.
Accordingly, the present invention also relates to method of treating or preventing a disease or condition in a mammal in need of such treatment wherein said disease or condition responds favorably to inhibition of PDE4 or production of TNF and is a member selected from the group consisting essentially of asthma; joint inflammation; rheumatoid arthritis; gouty arthritis; rheumatoid spondylitis; osteoarthritis; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; acute respiratory distress syndrome; cerebal malaria; chronic obstructive pulmonary disease (COPD), including asthma, chronic bronchitis and pulmonary emphysema; silicosis; pulmonary sarcoidosis; bone resorption diseases; reperfusion injury; graft vs. host reaction; allograft rejections; fever and myalgias due to bacterial, viral or fungal infection including influenza; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS); AIDS; HIV infection; ARC (AIDS related complex); keloid formation; scar tissue formation; Crohn""s disease; ulcerative colitis; pyresis; multiple sclerosis; type 1 diabetes mellitus; autoimmune diabetes; systemic lupus erythematosis; bronchitis; psoriasis; Bechet""s disease; anaphylactoid purpura nephritis; chronic glomerulonephritis; inflammatory bowel disease; leukemia; allergic rhinitis; and dermatitis, comprising administering to said mammal a therapeutically effective amount of a therapeutically active composition of matter comprising a compound of Formula (IA) or (IB), optionally together with a pharmaceutically acceptable carrier therefor.
The present invention further relates to a pharmaceutical composition for the prevention or treatment of the diseases and conditons enumerated above, especially including asthma, in a mammal, comprising a therapeutically effective amount of a compound according to Formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.
This invention further relates to a method of treating or preventing the foregoing specific diseases and conditions by administering to a patient an effective amount of a compound of Formula (IA) or (IB), or a pharmaceutically acceptable salt thereof. In particular, the present invention includes compounds useful in treating or preventing one or members selected from the groups of diseases and conditions consisting essentially of (1) inflammatory diseases and conditions comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn""s disease; (2) respiratory diseases and conditions comprising: acute respiratory distress syndrome, bronchitis, chronic obstructive pulmonary disease (COPD), including asthma, chronic bronchitis and pulmonary emphysema, and silicosis; (3) infectious diseases and conditions comprising: sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune diseases and conditions comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) other diseases and conditions comprising: bone resorption diseases; reperfusion injury; cachexia secondary to infection, malignancy, or to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia; wherein said compound comprises an inhibitor of phosphodiesterase isozyme 4 (PDE4).
Especially important among the above-recited diseases and conditions which may be treated or prevented using the compounds of the present invention are the inflammatory diseases and conditions and the respiratory diseases and conditions. Among the inflammatory diseases and conditions which are especially significant with regard to successful treatment or prevention using the compounds of the present invention comprise: joint inflammation, rheumatoid arthritis, osteoarthritis, Crohn""s disease, and inflammatory bowel disease. Among the respiratory diseases and conditions which are especially significant with regard to successful treatment or prevention using the compounds of the present invention comprise: chronic obstructive pulmonary disease (COPD), especially asthma and chronic bronchitis, as well as, acute respiratory distress syndrome.
The expression xe2x80x9ctreating or preventingxe2x80x9d, as used herein with regard to the administration of the compounds of the present invention for therapeutic purposes in the case of various members selected from the many groups of diseases and conditions specifically recited herein, is intended to denote both the therapeutic objective of said administration as well as the therapeutic results actually achieved by said administration. The extent of therapy accomplished by administration of the compounds of the present invention may range from an amelioration to a significant diminishing of the course of the disease involved, and beyond to active treatment of said disease, including a reversal of the disease process itself which is present. The higher or highest degrees of therapeutic effectiveness result in the prevention of any injury, damage, deterioration, or loss of body tissues or organs and basic body functions subsequent to the early stages of degeneration and decline in said body tissues or organs and basic body functions at the onset of the disease involved.
The expression xe2x80x9cthe early stages of degeneration and decline in body tissues or organs and basic body functionsxe2x80x9d is intended to mean the very beginning of the initial pathologic changes in said body tissues or organs and basic body functions which define and are the result of a disease process. Said pathologic changes with respect to tissues and organs include changes in the composition and cohesiveness; form and makeup; rigidity, strength, resilience, elasticity, conformational integrity and stability, density, tensile strength and other measures of physical quality; abundance and extent of its presence throughout the body; viability and regenerative capability on both a micro- and macro-level; and the ability to successfully resist various kinds of external stresses including mechanical force and invasion by microorganisms; of said tissues and organs from that present before the onset of said disease process, which result in a degradation and decline of the beneficial and necessary properties characterizing said tissues and organs.
Pathologic changes with respect to body functions are those which inherently arise from the changes above-described with respect to said tissues and organs, and which also, consequently, result in a degradation and decline in the beneficial and necessary performance which characterizes the normal and proper operation of said body functions. These pathologic changes, both with regard to tissues or organs and with respect to body functions, especially include improper repair of the above-discussed early stages of degeneration and decline.
Reaction Schemes 1-4 below illustrate the preparation of the compounds of the present invention: 
The compounds in the schematic representations above are numbered using Roman numerals in consecutive order, starting with II. These Roman numeral reference numbers are not necessarily related to the Roman numerals used elsewhere in defining the compounds of the present invention. Unless otherwise indicated, R and R1 in the reaction schemes are defined the same as elsewhere herein.
The preparation of compounds of Formula (IA) or (IB) can be carried out by one skilled in the art according to one or more of the synthetic methods outlined in Schemes 1-4 above and the examples referred to below. In Step 1 of Scheme 1, the carboxylic acid of Formula II, which is available from known commercial sources or can be prepared according to methods known to those skilled in the art, is nitrated under standard conditions of nitration (HNO3/H2SO4, 0xc2x0 C.) and the resulting nitro derivative of Formula III is hydrogenated in Step 2 of Scheme 1 using standard hydrogenation methods (H2-Pd/C under pressure) at ambient temperature (20-25xc2x0 C.) for several hours (2-10 hours) to provide the compound of Formula IV. In Step 3 of Scheme 1, the amino benzoic acid of Formula IV is reacted with a base such as sodium carbonate under aqueous conditions and gently heated until mostly dissolved. The reaction mixture is chilled to a lower temperature (about 0xc2x0 C.) and treated with sodium nitrate in water. After about 15 minutes, the reaction mixture is slowly transferred to an appropriate container holding crushed ice and a strong acid such as hydrochloric acid. The reaction mixture is stirred for 10-20 minutes and then added, at ambient temperature, to a solution of excess tert-butyl thiol in an aprotic solvent such as ethanol. The reaction mixture is acidified to a pH of 4-5 through addition of an inorganic base, preferably saturated aqueous Na2CO3, and the reaction mixture is allowed to stir at ambient temperature for 1-3 hours. Addition of brine to the reaction mixture, followed by filtration, provides the sulfide of Formula V.
In Step 4 of Scheme 1, the sulfide of Formula V is converted to the corresponding indazole carboxylic acid of Formula VI by reacting the sulfide of Formula V with a strong base, preferably potassium tert-butoxide, in dimethyl sulfoxide (DMSO) at ambient temperature. After stirring for several hours (1-4 hours), the reaction mixture is acidified with a strong acid, such as hydrochloric or sulfuric acid, and then extracted using conventional methods. In Step 5 of Scheme 1, the indazole carboxylic acid of Formula VI is converted to the corresponding ester of Formula VII by conventional methods known to those skilled in the art. In Step 6 of Scheme 1, the compound of Formula VII is provided through alkylation of the ester of Formula VII by subjecting the ester to conventional alkylation conditions (strong base/various alkylating agents and, optionally, a copper catalyst such as CuBr2) in a polar aprotic solvent, such as tetrahydrofuran (THF), N-methylpyrrolidinone or dimethylformamide (DMF), at ambient or higher temperature (25-200xc2x0 C.) for about 6-24 hrs, preferably about 12 hours. In Step 7 of Scheme 1, the compound of Formula VII is converted to the corresponding alcohol of IX by following conventional methods known to those skilled in the art for reducing esters to alcohols. Preferably, the reduction is effected through use of a metal hydride reducing agent, such as lithium aluminum hydride, in a polar aproptic solvent at a low temperature (about 0xc2x0 C.). In Step 8 of Scheme 1, the alcohol of Formula IX is oxidized to the corresponding aldehyde of Formula X according to conventional methods known to those skilled in the art. For example, the oxidation can be effected through use of a catalytic amount of tetrapropylammonium perrutenate and excess N-methylmorpholine-N-oxide, as described in J. Chem. Soc., Chem. Commun., 1625 (1987), in an anhydrous solvent, preferably methylene chloride.
Scheme 2 provides an alternative method of preparing the aldehyde of Formula X. In Step 1 of Scheme 2, the compound of Formula XI is nitrated using conventional nitration conditions (nitric and sulfuric acid) to provide the compound of Formula XII. In Step 2 of Scheme 2, the nitro derivative of Formula XII is reduced to the corresponding amine of Formula XIII according to conventional methods known to those skilled in the art. Preferably, the compound of Formula XII is reduced to the amine of Formula XII using anhydrous stannous chloride in an anhydrous aprotic solvent such as ethanol. In Step 3 of Scheme 2, the amine of Formula XIII is converted to the corresponding indazole of Formula XIV by preparing the corresponding diazonium fluoroforates as described in A. Roe, Organic Reactions, Vol. 5, Wiley, New York, 1949, pp. 198-206, followed by phase transfer catalyzed cyclization as described in R. A. Bartsch and I. W. Yang, J. Het. Chem. 21, 1063 (1984). In Step 4 of Scheme 2, alkylation of the compound of Formula XIV is performed using standard methods known to those skilled in the art, e.g., strong base, polar aprotic solvent and an alkyl halide, to provide the N-alkylated compound of Formula XV. In Step 5 of Scheme 2, the compound of Formula XV is subjected to metal halogen exchange employing an alkyl lithium, such as n-butyl lithium, in a polar aprotic solvent, such as THF, at low temperature (xe2x88x9250xc2x0 C. to 100xc2x0 C., with xe2x88x9278xc2x0 C. being preferred) followed by quenching with DMF at low temperature and warming to ambient temperature to provide the aldehyde compound of Formula X.
Scheme 3 illustrates the preparation of a compound of Formula XXII which is a compound of Formula (IA) or (IB) wherein R2a or R2b is a ring moiety of Formula (IC). In Step 1 of Scheme 3, the aldehyde moiety of the compound of Formula X is converted to an appropriate leaving group, such as a halogen, mesylate or another leaving group familiar to those skilled in the art, followed by reacting the resulting compound with sodium cyanate in a polar solvent such as DMF to provide the compound of Formula XVI. In Step 2 of Scheme 3, the compound of Formula XVI is reacted under basic conditions with methyl acrylate or related derivatives depending on the R2a or R2b group to be added, in an aprotic solvent such as ethylene glycol dimethyl ether (DME) at high temperature, preferably at reflux, to provide the compound of Formula XVII. In Step 3 of Scheme 3, the compound of Formula XVII is converted to the compound of Formula XVIII using a strong base, such as sodium hydride, and a polar aprotic solvent, such as DMF or THF, at elevated temperature, preferably at reflux.
In Step 4 of Scheme 3, the compound of Formula XVIII is decarboxylated using conventional methods, such as using sodium chloride in DMSO at a temperature of about 140xc2x0 C., to provide the compound of Formula XIX. In Step 5 of Scheme 3, derivatization of the compound of Formula XIX to the corresponding dithian-2-ylidine cyclohexane carbonitrile of Formula XX is done by reaction with 2-lithio-1,3-dithiane. In Step 5-a of Scheme 3, further derivatization of the compound of Formula XIX to the corresponding cyclohexane carbonitrile of Formula XXV which is para-substituted on the cyclohexane group with an hydroxyl moiety and an R4 substituent, e.g., methyl, is carried out by reacting the ketone with a nucleophilic reagent, e.g., an alkyllithium compound or a Grignard reagent in accordance with procedures well known in the art. In Step 5-b of Scheme 3, further derivatization of the compound of Formula XIX to the corresponding cyclohexane carbonitrile of Formula XXVI which is para-substituted on the cyclohexane group with an hydroxyl moiety, is carried out by reducing the ketone with, e.g., lithium aluminum hydride or sodium borohydride in accordance with procedures well known in the art. In Step 6 of Scheme 3, the compound of Formula XX is converted to the corresponding ester of Formula XXI using mercury (II) chloride and perchloric acid in a polar protic solvent such as methanol. In Step 7 of Scheme 3, the compound of Formula XXI is converted through hydrolysis to the corresponding carboxylic acid of Formula XXII using a standard method of hydrolysis, such as using aqueous sodium hydroxide in a polar solvent, or any of numerous existing hydrolysis methods known to those skilled in art as described in T. Green and P. G. M. Wets, Protecting Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons, New York (1991). The synthetic steps described for Scheme 3 are analogous to the synthetic methods provided for the preparation of corresponding catechol-containing compounds in PCT published applications WO 93/19751 and WO 93/17949.
Other compounds of Formula (IA) or (IB) wherein one of R2a or R2b is selected from moieties (IC), (ID), (IE) and (IF), can be prepared from one or more of the intermediate compounds described in Schemes 1-3. In particular, the aldehyde of Formula X or the keto compound of Formula XIX can be used to prepare various compounds of Formula (IA) or (IB). Any of the various R2a or R2b moieties of formulas (IC), (ID), (IE) or (IF) can be introduced into one or more of the intermediate compounds referred to above using synthetic methods provided for corresponding non-indazole analogs in PCT published applications WO 93/19748, WO 93/19749, WO 93/09751, WO 93/19720, WO 93/19750, WO 95/03794, WO 95/09623, WO 95/09624, WO 95109627, WO 95/09836, and WO 95/09837. For example, with reference to Step 1 of Scheme 4, the carboxylic acid of Formula XXII can be converted to the alcohol of Formula XXIII by reduction with various metal hydrides in a polar solvent as described in Example 9, referred to below, and in accordance with synthetic methods provided for corresponding non-indazole analogs in PCT published applications publication numbers WO 93/19747, WO 93/19749 and WO 95/09836. Further, with reference to Step 2 of Scheme 4, the carboxylic acid of Formula XXII can be converted to the corresponding carboxamide of Formula XXIV through conversion to an intermediate acid chloride using conventional synthetic methods, and then reacting the acid chloride with ammonia in an aprotic solvent. Other carboxamide analogs of Formula XXIV can be prepared through reaction of the acid chloride intermediate with various primary or secondary amines according to conventional methods known to those skilled in the art and as described in the PCT published applications referred to above.
Other compounds of Formula (IA) or (IB) can be prepared from the intermediate compound of Formula XIX in accord with synthetic methods provided for corresponding non-indazole analogs in the PCT published applications referred to above. Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of partial Formula (IC), and either R114 (R4) or R is H, can be prepared from the keto intermediate of Formula XIX by reaction with a base such as lithium diisopropylamine in a polar aprotic solvent, such as THF, and excess N-phenyltrifluoromethylsulfonamide as described in PCT published application WO 93/19749 for corresponding non-indazole analogs. Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of partial Formula (IC), R114 (R4) is hydrogen, and R115 (R5) is xe2x80x94CO2CH3 or xe2x80x94CO2H prepared from the keto intermediate of Formula XIX through reaction with triflic anhydride in the presence of a tertiary amine base followed by reaction of the resulting triflate with (triphenylphosphine)palladium and carbon monoxide in the presence of an alcohol or amine to provide the methyl ester compounds of Formula (IA) or (IB) wherein R115 (R5) is xe2x80x94CO2CH3. The methyl ester compound can be hydrolyzed to obtain the corresponding carboxylic acid compound by employing standard methods for hydrolysis such as sodium or potassium hydroxide in aqueous methanol/tetrahydrofuran. Such synthetic methods are further described in PCT published application WO 93/19749 for corresponding non-indazole analogs.
Other compounds of Formula (IA) or (IB) can be prepared from the intermediate compound of Formula XIX in accord with synthetic methods described for corresponding non-indazole analogs in the published PCT applications referred to above. Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of partial Formula (IC), R115(R5) is hydrogen, and R114(R4) is hydroxy, can be prepared through reaction of the intermediate of Formula XIX with an appropriate reducing agent such as lithium borohydride, diamyl borane, lithium aluminum tris(tert-butoxide), or sodium borohydride in a suitable non-reacting solvent such as 1,2-dimethoxy ethane, THF or alcohol. Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IC), R115 (R5) is hydrogen and R114 (R4) is xe2x80x94NH2, xe2x80x94NHCH3, or xe2x80x94N(CH3)2, can be prepared by reacting the intermediate of Formula XIX with an ammonium salt, such as ammonium formate, methylamine hydrochloride or dimethylamine hydrochloride, in the presence of sodium cyanoborohydride in an appropriate solvent such as alcohol.
Alternatively, compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IC), R114 (R4) is amino, and R115 (R5) is hydrogen, can be prepared by reacting the corresponding alcohol of Formula (IA) or (IB) where R14 (R4)=OH and R115 (R5)=H, with a complex of an azadicarboxylate ester in the presence of an imide or phthalimide followed by reaction in an alcoholic solvent such as ethanol. Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IC), R115 (R5) is H, and R114 (R4) is xe2x80x94SR124 can be prepared by reacting the corresponding compound wherein R114 (R4) is a leaving group such as mesylate, tosylate, bromine or chlorine, with a metal salt of mercaptan such as NaSR124 in an appropriate aprotic solvent. Corresponding compounds of Formula (IA) or (IB) wherein R14 (R4) is xe2x80x94SH can be prepared by reacting the corresponding alcohol R114 (R4)xe2x95x90OH, with a complex of a phosphine, such as triphenyl phosphine, and an azidocarboxylate ester in the presence of thiolacetic acid followed by hydrolysis of the resulting thiolacetate. Furthermore, compounds of this structure wherein R114 (R4) is hydroxy can be interconverted using a standard alcohol inversion procedure known to those skilled in the art. The foregoing compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IC), R115 (R5) is hydrogen, and R14 (R4) is hydroxy, xe2x80x94SH or xe2x80x94NH2, can be converted to various other compounds of Formula (IA) or (IB) through one or more synthetic methods described in PCT published applications WO 93/19751 and WO 93/19749 for corresponding non-indazole analogs.
Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IC) and the dashed line represents a double bond attached to the ring carbon atom to which substituent R113 (R3) is attached, can be prepared from the intermediate of Formula XIX by following one or more synthetic methods provided for the preparation of corresponding non-indazole analogs in PCT published application WO 93/19720. Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IC), and R114 (R4) and R115 (R5) are taken together to form =O or =R118, wherein R118 is as defined above, can be prepared from the corresponding ketone intermediate of formula XIX following one or more synthetic methods provided for corresponding non-indazole analogs in PCT published application WO 93/19750. Other compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IC) and R114 (R4) and R115 (R5) are taken together as xe2x95x90R118 can be prepared from the intermediate of Formula XIX following one or more synthetic methods provided for the preparation of corresponding non-indazole analogs in PCT published application WO 93/19748.
Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (ID) can be prepared from one or more of the intermediates referred to above, such as the bromoindazole intermediate of Formula XV, following one or more synthetic methods provided for the preparation of corresponding non-indazole analogs in PCT published applications WO 95/09627, WO 95/09624, WO 95/09623, WO 95/09836 and WO 95/03794. Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IE) can be prepared from the intermediate of Formula XV following one or more of synthetic methods provided for the preparation of corresponding non-indazole analogs in PCT published applications WO 95/09624 and WO 95/09837. Compounds of Formula (IA) or (IB) wherein R2a or R2b is a moiety of Formula (IF) can be prepared from the bromoindazole intermediate of Formula XV employing one or more synthetic methods provided for the preparation of the corresponding catechol-containing analogs in PCT published applications WO 95/09627, WO 95/09623 and WO 95109624.
Particularly preferred compounds of the present invention are those represented by Formulas (I-i) and (I-ii): 
A method for the preparation of the compound of Formula (I-ii) is described in further below-recited Example 23. It is also possible to prepare said compound in accordance with the synthesis method described in above-depicted Scheme 2 and Scheme 3, using as the starting material for said method the compound prepared as described in below-recited Example 20, and represented by Formula (XV-i): 
The preferred compound depicted in Formula (I-i)above may be prepared in accordance with the synthesis methods described in above-depicted Scheme 1, Scheme 2, and Scheme 3, and as further detailed in the below-recited Examples. Another, preferred, method of preparing said compound may also be employed, and is represented in the following synthesis Scheme 5, which is a more generalized representation of the above-mentioned preferred method of preparing said above-described preferred compound of the present invention. 
As illustrated, the starting material of Formula XXVIII is reacted with a hydrazine of Formula XXIX and the in situ product of Formula XXX is heated without separation to yield an indazole of Formula XXXI, which is in turn reacted with dicyanocyclohexane of Formula XXXII to yield the cyano-analog of said above-described preferred compound of Formula XXXIII.
In Step 1 of Scheme 5, the compound of Formula XXVIII is treated with a hydrazine derivative of Formula XXIX and an acid, preferably ammonium acetate, in a solvent such as heptane, tetrahydrofuran, xylenes, toluene, or mesitylene, or a mixture of two or more of the foregoing solvents, preferably toluene, to provide the compound of Formula XXX. In general, the compound of Formula XXX need not be separated or isolated from the reaction mixture.
In Step 2 of Scheme 5, the reaction mixture containing the compound of Formula XXX is heated at a temperature between about 75xc2x0 C. and about 200xc2x0 C., preferably between about 90xc2x0 and 120xc2x0 C., for a period of about 2 hours to 48 hours, preferably 12 hours, to provide the compound of Formula XXXI.
Alternatively, the process of Step 1 of Scheme 5 may be accomplished using a salt of the hydrazine derivative, such as the hydrochloride, hydrobromide, mesylate, tosylate, or oxalate salt of said compound, preferably the mesylate salt, which is reacted with a base, such as sodium or potassium acetate, in a solvent such as heptane, tetrahydrofuran, xylenes, toluene, or mesitylene, or a mixture of two or more of the foregoing solvents, preferably toluene.
In Step 3 of Scheme 5, the compound of Formula XXXI is treated with the compound of Formula XXXII in the presence of a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, or lithium 2,2,6,6-tetramethylpiperidine, preferably potassium bis(trimethylsilyl)amide, in a solvent such as tetrahydrofuran, toluene, or xylenes, preferably toluene, at a temperature between about 25xc2x0 C. and about 125xc2x0 C., preferably about 100xc2x0 C., for a period 1 hour to 15 hours, preferably 5 hours, to provide compound of Formula XXXIII.
In Step 4 of Scheme 5, the compound of Formula XXXIII is treated with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, or trifluoromthanesulfonic acid, preferably hydrochloric acid, in a solvent of the Formula XXXIV, ie., R124xe2x80x94OH wherein R124 is as defined herein, e.g., (C1-C6) alkyl, such as methanol, ethanol, propanol, isopropanol, preferably ethanol, at a temperature between 0xc2x0 C. and 50xc2x0 C., preferably ambient temperature (20-25xc2x0 C.) for a period of 1 hour to 48 hours, preferably 14 hours, to provide a compound of Formula XXXV. In general, the compound of Formula XXXV need not to be separated or isolated from the reaction mixture.
In step 5 of Scheme 5, the compound of Formula XXXV is treated with water in a solvent such as toluene, ethyl acetate, diisopropyl ether, methyl tert-butyl ether, or dichloromethane, preferably toluene, at a temperature between about 0xc2x0 C. and 50xc2x0 C., preferably ambient temperature (20-25xc2x0 C.) for a period of 1 hour to 24 hours, preferably 8 hours, to provide a compound of Formula XXXVI.
A particular version of the synthesis of Scheme 5 above carried out with reactants suitable for obtaining the preferred cyclohexanecarboxylic acid compound of the present invention, is illustrated below in Scheme 6: 
Scheme 7 set out below illustrates a procedure to facilitate the handling and purification of the indazole intermediate of Formula XXXI which is described above in reference to Scheme 5. In Step 1 of Scheme 7, the indazole of Formula XXXI is treated with an acid, such as hydrobromic, hydrochloric, or sulfuric acid, preferably hydrobromic acid, in a solvent such as toluene, xylenes, acetic acid, or ethyl acetate, preferably toluene, at a temperature ranging from 0xc2x0 C. to ambient temperature (20-25xc2x0 C.), preferably ambient temperature, to form a salt of the compound of Formula XXXVIII, wherein HX indicates the acid used to prepare the salt and X is the anion of said acid. The salt may be separated and purified according to methods familiar to those skilled in the art. In Step 2 of Scheme 7, the salt is converted back to the free base. In this step, the salt of the compound of Formula XXXVIII is treated with an aqueous base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate, preferably sodium hydroxide, in a solvent such as hexane, toluene, dichloromethane, diisopropyl ether, methyl tert-butyl ether, or ethyl acetate, preferably toluene, at a temperature ranging from 0xc2x0 C. to ambient temperature (20-25xc2x0 C.), preferably ambient temperature, for a period of 5 minutes to 1 hour, preferably 20 minutes, to provide the compound of Formula XXXI. 
The compounds of the Formulas XXVIII-XXXVIII may have asymmetric carbon atoms and therefore exist in different enantiomeric forms. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers may be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound, e.g., alcohol, separating the diastereomers and converting, e.g., hydrolyzing, the individual diastereomers to the corresponding pure enantiomers. The use of all such isomers, including diastereomer mixtures and pure enantiomers, are considered to be part of the present invention.
Further details concerning the above-identified synthesis methods which are preferred for preparing the above-recited preferred compound of the present invention may be found in copending provisional U.S. Ser. No. 60/064,211 (Attorney Docket No. PC10004), filed Nov. 4, 1997, which is incorporated herein by reference in its entirety.
Pharmaceutically acceptable acid addition salts of the compounds of this invention include, but are not limited to, those formed with HCl, HBr, HNO3, H2SO4, H3PO4, CH3SO3H, p-CH3C6H4SO3H, CH3CO2H, gluconic acid, tartaric acid, maleic acid and succinic acid. Pharmaceutically acceptable cationic salts of the compounds of this invention of Formula (IA) or (IB) wherein, for example, R3 is CO2R9, and R9 is hydrogen, include, but are not limited to, those of sodium, potassium, calcium, magnesium, ammonium, N,Nxe2x80x2-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, and diethanolamine.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of a compound of Formula (IA) or (IB) or a pharmaceutically acceptable salt thereof (the active compounds) are generally in the range of 0.1-1000 mg daily for an average adult patient (70 kg). Individual tablets or capsules should generally contain from 0.1 to 100 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1% (w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.
For administration to humans for the inhibition of TNF, a variety of conventional routes may be used including orally, parenterally, topically, and rectally (suppositories). In general, the active compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substance; for example, enough salts or glucose to make the solution isotonic.
Additionally, the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice.
The active compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The active compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The active compounds may also be administered to animals by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
The ability of the compounds of Formula (IA) or (IB) or the pharmaceutically acceptable salts thereof to inhibit PDE4 may be determined by the following assay.
Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4 Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenized using a Tekmar Tissumizer(copyright) (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at full speed for 30 seconds. The homogenate is centrifuged at 48,000xc3x97g for 70 minutes at 4xc2x0 C. The supernatant is filtered twice through a 0.22 mm filter and applied to a Mono-Q FPLC column (Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, N.J. 08854) pre-equilibrated with pH 7.4 Tris/PMSF Buffer. A flow rate of 1 ml/minute is used to apply the sample to the column, followed by a 2 ml/minute flow rate for subsequent washing and elution. Sample is eluted using an increasing, step-wise NaCl gradient in the pH 7.4 Tris/PMSF buffer. Eight ml fractions are collected. Fractions are assayed for specific PDE4 activity determined by [3H]cAMP hydrolysis and the ability of a known PDE4 inhibitor (e.g. rolipram) to inhibit that hydrolysis. Appropriate fractions are pooled, diluted with ethylene glycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at xe2x88x9220xc2x0 C. until use.
Compounds are dissolved in dimethylsulfoxide (DMSO) at a concentration of 10 mM and diluted 1:25 in water (400 mM compound, 4% DMSO). Further serial dilutions are made in 4% DMSO to achieve desired concentrations. The final DMSO concentration in the assay tube is 1%. In duplicate the following are added, in order, to a 12xc3x9775 mm glass tube (all concentrations are given as the final concentrations in the assay tube).
i) 25 ml compound or DMSO (1%, for control and blank)
ii) 25 ml pH 7.5 Tris buffer
iii) [3H]cAMP (1 mM)
iv) 25 ml PDE4 enzyme (for blank, enzyme is preincubated in boiling water for 5 minutes)
The reaction tubes are shaken and placed in a water bath (37xc2x0 C.) for 20 minutes, at which time the reaction is stopped by placing the tubes in a boiling water bath for 4 minutes. Washing buffer (0.5 ml, 0.1M 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1M naci, pH 8.5) is added to each tube on an ice bath. The contents of each tube are applied to an AFF-Gel 601 column (Biorad Laboratories, P.O. Box 1229, 85A Marcus Drive, Melvile, N.Y. 11747) (boronate affinity gel, 1 ml bed volume) previously equilibrated with washing buffer. [3H]cAMP is washed with 2xc3x976 ml washing buffer, and [3H]5xe2x80x2 AMP is then eluted with 4 ml of 0.25M acetic acid. After vortexing, 1 ml of the elution is added to 3 ml scintillation fluid in a suitable vial, vortexed and counted for [3H].       %    ⁢          xe2x80x83        ⁢    inhibition    =      1    -                  average        ⁢                  xe2x80x83                ⁢                  cpm          (                                    test              ⁢                              xe2x80x83                            ⁢              compound                        -                          average              ⁢                              xe2x80x83                            ⁢                              cmp                ⁡                                  (                  blank                  )                                                                                          average          ⁢                      xe2x80x83                    ⁢                      cpm            ⁡                          (              control              )                                      -                  average          ⁢                      xe2x80x83                    ⁢          cpm          ⁢                      xe2x80x83                    ⁢                      (            blank            )                              
IC50 is defined as that concentration of compound which inhibits 50% of specific hydrolysis of [3H]cAMP to [3H]5xe2x80x2AMP.
The ability of the compounds I or the pharmaceutically acceptable salts thereof to inhibit the production TNF and, consequently, demonstrate their effectiveness for treating disease involving the production of TNF is shown by the following in vitro assay:
Peripheral blood (100 ml) from human volunteers is collected in ethylenediamine-tetraacetic acid (EDTA). Mononuclear cells are isolated by FICOLL/Hypaque and washed three times in incomplete HBSS. Cells are resuspended in a final concentration of 1xc3x97106 cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1xc3x97106 cells in 1.0 ml in 24-well plates. The cells are incubated at 37xc2x0 C. (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds (10 ml) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10 ml) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37xc2x0 C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (RandD Quantikine Kit). IC50 determinations are made for each compound based on linear regression analysis.
The following Examples further illustrate the invention, but they are not intended to be, nor should they be taken as in any way a limitation of the present invention. In the following examples, xe2x80x9cDMFxe2x80x9d means dimethylformamide, xe2x80x9cTHFxe2x80x9d means tetrahydrofuran, xe2x80x9cDMSOxe2x80x9d means dimethyl sulfoxide, and xe2x80x9cDMAPxe2x80x9d means 4-dimethylaminopyridine.